1. Field of the Invention
The invention relates to sustained-release coated-bead compositions containing a drug for oral administration, capsules filled therewith and method of preparation thereof wherein the drug is highly soluble in gastric fluid and much less soluble in intestinal fluid.
2. Information Disclosure Statement
Harrison et al. U.S. Pat. No. 4,806,361 issued Feb. 21, 1989 describes (column 3, lines 48-68)
. . . a sustained-release unit dosage form of a medicament of the 1,2-dihydro-3-cyano-6-lower-alkyl-5-(4-pyridinyl)-2(1H)-pyridinone class for oral administration comprising beads composed of an inert particulate core having adhered thereto a coating comprising said medicament, wherein each bead of said medicament-coated inert particulate core is surrounded by a sustaining coating comprising at least three admixed polymers, one of said polymers being soluble in gastric juices at all pH values normally encountered, a second of said polymers being insoluble in gastric juices at pH values below about 5 but soluble therein at pH values of about 5 and above and the third of said polymers being insoluble in the contents of the gastrointestinal tract at all pH values normally encountered, the portions as to permit a substantially uniform release of the medicament present notwithstanding the differing solubilities at the differing pH values prevailing during passage of the beads through the stomach and the gastrointestinal tract of a patient.
1,2-Dihydro-3-cyano-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone is the preferred 1,2-dihydro-3-cyano-6-lower-alkyl-5-(4-pyridinyl)-2(1H)-pyridinone. Hydroxypropylmethylcellulose is the preferred first polymer, which may also be polyvinylpyrrolidone or sodium carboxymethylcellulose. Hydroxypropylmethylcellulose phthalate is the preferred second polymer, which may also be a copolymer of the lower alkyl methacrylates. Ethylcellulose is the preferred third polymer, which may also be a copolymer of the lower alkyl methacrylates in which the copolymerising monomer contains a hydrophilic group. An adhesive, for example hydroxypropylmethylcellulose, is used to adhere the medicament to the particulate core.
The invention has the following advantages over the prior art including the compositions of Harrison et al. U.S. Pat. No. 4,806,361: 1) use of a toxic organic solvent, methylene chloride, is avoided; 2) the process of preparation is less sensitive to process variations; 3) the sustained release film has better mechanical strength; and 4) use of two portions of beads, one containing an immediate release dose and one containing a sustained release dose, is avoided.